It was the role of Yussel that brought Krumholtz to the attention of actor and filmmaker Edward Burns, who cast him in the independent film Sidewalks of New York (2001).[2] Playing the romantic and slightly obsessed Benny, Krumholtz was on a path to larger, more complex film roles. His first role as a leading man was in the romantic comedyYou Stupid Man (2002), opposite Milla Jovovich. Although never released theatrically in the United States, You Stupid Man, directed by Edward Burns's brother Brian Burns, was released on DVD (2006). Krumholtz carried his first leading role in a released American film when he starred Big Shot: Confessions of a Campus Bookie (2002), which premiered on FX Networks.

In 2012, Krumholtz was cast opposite Michael Urie in CBS' comedy TV series Partners[11] but the show was cancelled after six episodes.[12] In 2015, he played the titular role wearing heavy prosthetics as an elderly Jewish woman in the IFC comedy series Gigi Does It.

He had a prominent recurring role as adult filmmaker Harvey Wasserman in the first two seasons of the HBO drama series The Deuce, before being promoted to a series regular for the third season. In 2020, he appeared as a series regular playing Monty Levin in the HBO miniseries The Plot Against America.

Starting in 2020, Krumholtz began releasing rap music with the group Hemogoblin under the moniker Beengod Stillgod.[13]

He appeared in two documentaries on the Knocked Up DVD (one being staged and the other being genuine). "Gummy: The Sixth Roommate" tells the true story of how David dropped out of the film to play the lead part in a Woody Allen movie in Paris that got canceled before production, and Apatow would not write him back into his script. He would have played one of the main character's five roommates (along with other Freaks and Geeks alumni Seth Rogen, Jason Segel and Martin Starr).[14][15] Friend and fellow Freaks actor Jason Segel appears with him in a short scene in Tenacious D in The Pick of Destiny.

On May 22, 2010, Krumholtz married actress Vanessa Britting (born Vanessa Almeda Goonan), at The Plaza Hotel, in New York City; they had been engaged since July 2008.[16] They have a daughter, Pemma Mae Krumholtz, who was born in 2014, and a son, Jonas, born in 2016.[17]

In July 2011, Krumholtz was diagnosed with thyroid cancer. He began a radioactive iodine treatment five months later.[18] At the end of January 2012, he was pronounced cancer-free.[19]